Abstract 1225: Invalidation Of Monoamine Oxidase A Induces Dilated Cardiomyopathy And Exacerbates Cardiac Hypertrophy In Response To Pressure-overload
Background- Elevations of serotonin (5-HT) concentrations have been suggested to exert deleterious effects in the heart. Monoamine oxidase type A (MAO-A) is a key point in controlling 5-HT concentrations as it represents the major catabolic pathway for 5-HT degradation. In addition, MAO-A is responsible for the generation of hydrogen peroxide (H202) during degradation of 5-HT, which mediates cardiomyocytes hypertrophy in vitro. We hypothesized that MAO-A could play an important role in cardiac hypertrophy, either by regulating 5-HT levels in the heart, or by generating H202.
Methods and Results- In this study, we analyzed cardiac consequences of MAO-A invalidation in mice at baseline and after pressure overload-induced hypertrophy in the model of ascendant aortic banding. MAO-A invalidation resulted in 1.9 fold increase in cardiac 5-HT. MAO-A KO mice displayed dilated cardiomyopathy, with significant increase in end-diastolic and end-systolic dimensions (Table⇓). Additionally, KO mice displayed interstitial fibrosis (2.86 fold over WT, p= 0.02), along with reexpression of cardiac fetal gene program, a marker of cardiac remodeling. Markedly, aortic banding in MAO-A KO mice produced exacerbation of hypertrophic phenotype compared with age-matched WT mice. Echocardiographs demonstrated greater increase in intraventricular septum thickness and posterior wall thickness in banded KO compared to WT animals (Table⇓). Heart and ventricle to body weight ratios, along with cardiomyocytes cross-section areas, and hypertrophic markers ANF and Î2-MHC, demonstrated greater increase in KO compared to WT animals.
Conclusions-In this study, we show that MAO-A plays a key point in controlling cardiac 5-HT. In addition, we demonstrate that MAO-A invalidation is associated with cardiac dilatation and fibrosis, and exacerbates hypertrophy during pressure overload. These results provide evidence for a role of MAO-A/5-HT axis in regulating cardiac hypertrophy in vivo.